Evidence of the occurrence of immunogenic tumours among a majority is of different types of human cancers is increasing, e.g., specific cytotoxic T-lymphocytes, CTLs, are found in the blood of cancer patients, antibodies against tumour associated antigens have been identified, inflammatory cells are infiltrating the tumours, there is often a correlation between these cells and prognosis or response to immunotherapy and an immune mediated anti-tumour reactivity has been demonstrated after therapy.
The function of immune cells in cancer patients is, however, often impaired. Generally this is more pronounced in tumour infiltrating mononuclear cells (Vose et al., 1977), TIMC, than in cells obtained from peripheral blood. It has for example repeatedly been demonstrated that the proliferative response to mitogens, such as phytohemagglutinin (PHA) or concanavalin A (ConA), is inhibited, natural killer cell (NK-cell) activity and cytotoxic activity of CTLs are reduced as is the maturation and function of dendritic cells and the immune balance seems to be directed to a T-helper 2 situation (Pawelec et al. 2000).
Immunosuppression of TIMC can, however, at least to some extent be overcome, either by washing, preincubation before stimulation, or culturing in interleukin-2. Amazingly, the down-regulation of the immune system, which relates to cancer, does not result in a seriously increased incidence of infectious diseases in these patients.
The demonstration of concomitant immunity shows the existence of regional immunosuppression in the absence of systemic suppression, indicating a regional—systemic gradient of immunosuppression (North, 1985). Systemic immunosuppression can thus be regarded as a systemic dissemination, or “spill-over” of intra-tumoural suppression.
Extracts or supernatants from tumours are often immunosuppressive (Sulitzeanu, 1993). Several factors have been suggested to mediate this suppression, e.g., TGF-β, PGE2, IL-10, IL-4 and others, either being produced by the tumour cells as such or by tumour-infiltrating lymphocytes (TIL) or tumour associated macrophages (TAM) (e.g. Ménétrier-Caux et al., 1999; Heimdal et al., 2000; Heimdal et al., 2001). However, no fundamental mechanism has been identified so far (Mocellin, 2001).
The immunosuppression of cancer patients described above often involves an ongoing systemic, chronic inflammation with an increased production of cytokines, in particular IL-6 and TNF-αseems to be important mediators in this process. This results in a paraneoplastic syndrome with a poor performance status—impaired general condition, which is characterized by anorexia, fatigue, subfebrility and distortion of various biochemical laboratory parameters, e.g., low haemoglobin concentration, high numbers of platelets, increased numbers of blood monocytes, increased concentration of acute phase reactants, increased c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and other factors (Barton™, 2001; Blay et al., 1992; Blay et al., 1997; Gadducci et al., 2001; Walther et al., 1998). This condition is correlated to the tumour burden of the patient, being worse in more advanced disease. In the clinical situation, attempts are often made to ameliorate the poor general condition of these patients by corticosteroid treatment.
Chronic inflammatory reactions in cancer patients often result in a poor response to the immunotherapy (Blay et al. 1992; Deehan et al., 1994; Lissoni et al., 1999; Tartour et al., 1996). There are some animal and human reports on the importance of the immune status of tumour bearers for response to cytotoxic treatment/chemotherapy or radiotherapy. (Goldin et al., 1980; Milas et al., 2001)
Immunostimulatory treatment of the dysregulated immune system of cancer patients might be counter-productive. If the immune system in cancer is directed to down-regulation of the chronic inflammatory reaction there is a risk that further therapeutic immunostimulation will enhance the immunosuppression and thereby further down-regulate the immune reactivity against the tumour cells. The strategy should therefore be to eliminate mediators of immunosuppression before the immune system is stimulated.
In developing immunotherapeutic strategies in cancer several critical steps, of major importance for initiation and maintenance of immune mediated anti-tumour reactivity, have to be considered.
For initiation of an immune response the tumour has to be recognised as non-self. The initial induction of an immune response to tumour associated antigens takes place at an early stage of the malignant disease while the tumour burden is still reasonably small and tumour related immunosuppressive mechanisms are not yet activated. In this situation the immune reactivity to the tumour is beneficial and control the malignant growth for some time.
In order to get an immune response a proper interaction between antigen presenting cells (APCs) and lymphocytes has to take place with a well-orchestrated production of cytokines and expression/interaction of co-stimulatory molecules.
In cancer patients with macroscopic, progressive tumour a different situation prevails. The anti-tumour immune reactivity has been suppressed. In a small subset of patients the immunostimulatory therapeutic strategies, which are available, e.g., interferons, interleukins, vaccination, can overcome this immunosuppression, which results in objective tumour regression in only about 10-15 percent of the patients and short-lasting minor regressions in some more. The poor efficacy of such treatment strategy depends on the occurrence of non-immunogenic tumours, serious immunosuppression (which can not be overcome by current therapeutic methods) and down-regulation of the immune reactivity during immunotherapy. Tumour related suppressor substances might interfere with these mechanisms during development of immunosuppression. Immune mediated anti-tumour reactivity also seems to be down regulated via interaction with FcR, in particular FcγR.
Tumour related immunosuppression takes place at four levels: Activation, recruitment of effector cells to the tumour, migration of these cells from stromal areas close to the tumour cells and cytotoxic activity.
Mechanisms by which malignant tumours can down-regulate the immune system are                tumour derived non-immunogenic substances with suppressor activity;        well-characterized immunomodulating substances, cytokines, e.g., transforming growth factor beta (TGF-β), IL-10, as well as PGE2,        tumour associated antigen (TAA) resulting in antigenic overload, production of antibody and immunocomplex (IC);        serum blocking factors, which are probably related to immune complexes, cross-linking Fc receptor (FcγR);        proteolytic fragments from tumour substances, e.g., extracellular matrix (ECM);                    T-helper 1/T helper 2 (Th1/Th2) balance                        
Stimulation of the inhibited immune reactivity to the tumour can be achieved using several therapeutic strategies. However, several function parameters are down-regulated during the treatment, particularly in tumour areas with the most pronounced regressive changes.
It would thus be of great importance in the treatment of cancer patients to identify the mechanisms by which the immune system is dys-regulated and to develop proper diagnostic tests of this condition. The ultimate goal is then, based on these tests to find measures to treat, eliminate the immunosuppression, and thereby improve the general condition of cancer patients and increase the therapeutic efficacy in cancer.